ABSTRACT
Vaccine Trials ..................................................................................233 11.5.3 Case Example of Using the Meta-Analytic Predictive
Approach .........................................................................................236 11.6 Conclusion ..................................................................................................238 Acknowledgments .............................................................................................. 239 References ............................................................................................................. 239
ABSTRACT A general agreement exists in the eld of research and development of clinical trials that a gold standard for evaluating treatment efcacy of a medical product is the use of placebo as a comparator. Over the years, researchers and practitioners have argued that placebo controls are controls, often citing the following sentence in the Declaration of Helsinki (Ref) as support for their position: “In any medical study, every patient-including those of a control group, if any-should be assured of the best proven diagnostic and therapeutic method.” However, when the use of placebo is considered to be unethical or impractical, a viable alternative for evaluating treatment efcacy is through a noninferiority (NI) study where the aim is to demonstrate that the test treatment (drug or biologic) is no worse than the comparator by more than a prespecied, small amount. This amount, known as the NI margin, is small enough to allow the known effectiveness of the active control to support the conclusion that the new test treatment is also effective. The minimal objective of a clinical trial involving hypothesis of superiority is to determine whether the test treatment is superior to placebo. An assumption is made that if the active control treatment remains efcacious, as was observed when it was compared with placebo, then a test treatment that has comparable efcacy with the active control, within a certain range, must also be superior to placebo. Because of this assumption, the design, implementation, and analysis of NI trials present challenges for sponsors and regulators. One such challenge is to build a methodology that can consolidate existing substantial historical data, which is often required on the active control treatment and placebo. Bayesian approaches provide a natural framework for synthesizing and quantifying the historical data in the form of prior distributions that can effectively be used to address directly key questions in design and analysis of a NI clinical trial. In the case of showing biosimilarity, that is, showing that the biological product is highly similar to the reference product in terms of safety, purity, and potency, having full knowledge of the reference product is pertinent to successfully carry out the trials. Thus, it requires a methodology like Bayesian methods for generating relevant summaries of historical data based on the reference product. Our primary objective of this chapter is to show how Bayesian methods can be appropriately carried out in the design and analysis of clinical trials involving NI hypothesis.
